The present invention relates to a novel process for the preparation of R-(+)-6-carboxamido-3-N-methylamino-1,2,3,4-tetrahydrocarbazole.
WO-A-93/00086 describes a group of tetrahydrocarbazole derivatives, which have activity as 5HT1 receptor agonists and are therefore useful in the treatment of migraine. The specific compounds disclosed include inter alia 3-methylamino-6-carboxamido-1,2,3,4-tetrahydrocarbazole hydrochloride. WO-A-93/00086 also describes a preparation of 3-methylamino-6-carboxamido-1,2,3,4-tetrahydrocarbazole hydrochloride which comprises a six stage process, via 3-methylamino-6-cyano-1,2,3,4-tetrahydrocarbazole, involving a number of protection and deprotection steps.
WO-A-94/14772 describes enantiomers of certain carbazole derivatives, including the aforementioned compound. The enantiomers disclosed are:
R-(+)-6-carboxamido-3-N-methylamino-1,2,3,4-tetrahydrocarbazole;
S-(xe2x88x92)-6-carboxamido-3-N-methylamino-1,2,3,4-tetrahydrocarbazole;
R-(+)-6-carboxamido-3-N-ethylamino-1,2,3,4-tetrahydrocarbazole;
S-(xe2x88x92)-6-carboxamido-3-N-ethylamino-1,2,3,4-tetrahydrocarbazole;
and 3 salts and solvates thereof.
R-(+)-6-carboxamido-3-N-methylamino-1,2,3,4-tetrahydrocarbazole succinate has now entered clinical trials for the treatment of migraine.
WO-A-94/14772 provides various methods by which single enantiomers can be prepared, namely:
(i) separation of an enantiomeric mixture of the compound or a derivative thereof by chromatography, e.g. on a chiral HPLC column;
(ii) separation of diastereoisomers of a chiral derivative (e.g. a chiral salt) of the compound e.g. by crystallisation or chromatography; or
(iii) alkylation of (+) or (xe2x88x92) enantiomer of 3-amino-6-carboxamido-1,2,3,4-tetrahydrocarbazole or a salt thereof.
Although the above-noted procedures (i) to (iii) can be used to prepare the desired enantiomer, they are disadvantageous from the point of view of xe2x80x9cscale-upxe2x80x9d and the manufacture of commercial quantities of the compound. In particular it has been found that carrying out the resolution at the final stage of the synthesis and using R-2-pyrrolidone-5-carboxylic acid (also known as D-pyroglutamic acid) to form a chiral salt results in an intermediate with poor solubility and hence gives low yields of the desired enantiomer, despite the fact that R-2-pyrrolidone-5-carboxylic acid is described as a preferred optically active acid for use in the process described in WO-A-94/14772.
There is therefore a need to provide a more efficient method which more readily lends itself to commercial manufacture. We have now devised such a process for the preparation of R-(+)-6-carboxamido-3-N-methylamino-1,2,3,4-tetrahydrocarbazole. This process relies on resolution of an indole nitrile intermediate compound at a relatively early stage of the process. We have surprisingly found that this intermediate has good solubility and enables the desired enantiomer to be obtained in good yield. Indeed, although the new process has one more step than the process of WO-A-94/14772 it gives a greater overall yield of final product. Furthermore, carrying out the resolution on the nitrile intermediate ensures that subsequent steps are carried out on the correct enantiomeric form of intermediate compounds resulting in direct production of the compound without the need for chromatography or the like.
Thus, in a first aspect, the present invention provides a process for the preparation of R-(+)-6-carboxamido-3-N-methylamino-1,2,3,4-tetrahydrocarbazole which comprises the step of resolving a mixture of enantiomers of an indole nitrile compound of formula (I): 
The compound of formula (I) may be named as 6-cyano-3-N-methylamino-1,2,3,4-tetrahydrocarbazole. It will be appreciated that the compound of formula (I) may comprise varying ratios of its two enantiomers. In particular it may exist as a racemic mixture.
It has been found that resolution of the mixture of indole nitrile enantiomers can advantageously be achieved by the use of L-pyroglutamic acid. Indeed, it was surprisingly found that use of D-pyroglutamic acid gave the xe2x80x98wrongxe2x80x99 enantiomer, whereas L-pyroglutamic acid gave the desired enantiomer in good yield. The use of L-pyroglutamic acid also has economic advantages as it is the naturally occurring form and hence considerably less expensive than the D-form. Reaction with the optically active acid to form a chiral salt may be effected in a suitable solvent, for example an alcohol such as methanol or ethanol and at a temperature in the range 0 to 100xc2x0 C. The desired enantiomer is obtained by crystallisation using methods well known in the art. Crystallisation may be initiated spontaneously, or in some cases seeding may be required. The reaction mixture is desirably treated with acetic acid, preferably after crystallisation has been initiated. This has been found advantageously to facilitate selective crystallisation of the desired enantiomer. The resulting L-pyroglutamate salt may advantageously be recrystallised from aqueous methanol or more preferably aqueous ethanol to enhance the optical purity of the product. The chiral salt may be converted into the free base using standard procedures, to provide (+)-6-cyano-3-N-methylamino-1,2,3,4-tetrahydrocarbazole. If desired this compound may be directly reacted in situ to form the corresponding carboxamido compound.
(+)-6-Cyano-3-N-methylamino-1,2,3,4-tetrahydrocarbazole is a novel compound. Therefore, in a further aspect the present invention provides (+)-6-cyano-3-N-methylamino-1,2,3,4-tetrahydrocarbazole of formula (II): 
and salts and solvates thereof.
A preferred embodiment of this aspect of the invention is (+)-6-cyano-3-N-methylamino-1,2,3,4-tetrahydrocarbazole L-pyroglutamate.
The compound of formula (II) may be converted into the desired R-(+)-6-carboxamide-3-N-methylamino-1,2,3,4-tetrahydrocarbazole or a salt or solvate thereof.
In a further aspect therefore, the present invention provides a process for the preparation of R-(+)-6-carboxamido-3-N-methylamino-1,2,3,4-tetrahydrocarbazole or a salt or solvate thereof, which process comprises hydrolysing R-(+)-6-cyano-3-N-methylamino-1,2,3,4-tetrahydrocarbazole or a salt or solvate thereof. As will be readily apparent to those skilled in the art, a nitrile may be hydrolysed to give either an amide or a carboxylic acid, depending upon the conditions used. It will therefore be appreciated that in the present process the hydrolysis conditions should be chosen to give an a mide rather than a carboxylic acid. Preferably hydrolysis is effected using acetic acid and boron trifluoride (BF3)/acetic acid complex. Other means of hydrolysis which may be employed include hydrogen peroxide in the presence of an alkali hydroxide, such as sodium hydroxide, in a solvent such as an alcohol; or formic acid and hydrobromic or hydrochloric acid.
6-Cyano-3-N-methylamino-1,2,3,4-tetrahydrocarbazole employed as the starting material for the resolution step, may be prepared for example using the methods described in WO-A-93/00086. Alternatively, and more preferably 6-cyano-3-N-methylamino-1,2,3,4-tetrahydrocarbazole may be prepared by reacting 4-cyanophenyl hydrazine of formula (III): 
or a salt thereof e.g. the hydrochoride with 4-methylaminocyclohexanone or a protected derivative thereof. Advantageously the ketal derivative 4-methylaminocyclohexanone (2xe2x80x2,2xe2x80x2-dimethyltrimethylene)ketal or a salt thereof, eg the hydrochloride, is employed: 
The reaction is preferably effected under aqueous acidic conditions.
The aforementioned ketal derivative (IV) is a commercially available compound. It may be prepared for example by the method described in WO-A-94/14772, by reaction of the corresponding protected 1,4-cyclohexanedione of formula (V): 
with methylamine.
The reaction is preferably effected in a suitable solvent, such as an alcohol, or a mixture thereof, e.g. industrial methylated spirits or methanol, with catalytic hydrogenation using for example palladium on charcoal.
A complete synthetic sequence from the keto-ketal of formula (V) to R-(+)-6-carboxamido-3-N-methylamino-1,2,3,4-tetrahydrocarbazole is as follows: 
Preferred reaction conditions for the various steps are as follows:
(i) IMS, MeNH2, H2, Pdxe2x80x94C then THF, HCl, 0-10xc2x0 C. e.g. 0-5xc2x0 C. or preferably 5-10xc2x0 C. (yield: 77-94% theory);
(ii) HCl(aq), 80-90xc2x0 C. preferably 85-90xc2x0 C. followed by 0-5xc2x0 C. then NaOH(aq), THF followed by 0-5xc2x0 C., (yield: 62-85% theory);
(iii) MeOH, L-pyroglutamic acid (L-PGA), AcOH, 50xc2x0 C. or preferably reflux followed by 0-5xc2x0 C. then recrystallization from aqueous MeOH or preferably EtOH, (yield: 14-30% theory);
(iv) AcOH, BF3(AcOH)2, 90-95xc2x0 C. then NaOH, BuOH, then Na2CO3 or preferably water wash, (yield: 70-100% theory).
As an optional step (v) the resulting compound (II) from step (iv) can easily be converted to an appropriate salt form, e.g. a succinic acid salt by reaction with succinic acid in an alcohol such as ethanol or a mixture of alcohols such as ethanol and butanol. The reaction is preferably effected at a temperature in the range 60-100xc2x0 C. eg 60-65xc2x0 C. or preferably 70-100xc2x0 C. then 20-25xc2x0 C., (yield: 87-90% theory). The salt, eg the succinate may if desired or necessary be recrystallised, preferably using aqueous ethanol.
In a further embodiment therefore the present invention provides a process for the preparation of R-(+)-6-carboxamido-3-N-methylamino-1,2,3,4-tetrahydrocarbazole or a salt or solvate thereof, which comprises reaction steps (i) to (iv) above and optionally salt formation step (v).
As the amine ketal hydrochloride material used in step (ii) is a commercially available compound, the process can effectively consist of only steps (ii) to (iv).
In another aspect the present invention provides the use of L-pyroglutamic acid in resolving an enantiomeric mixture of an indole nitrile compound of the formula (I): 